ESPE Abstracts (2014) 82 FC13.6

Abnormal Thyroid Hormone Metabolism in Patients with THRA Mutations due to Impaired Expression of the Type 3 Deiodinase

Anja van Guchta, Alies van Mullema, Sigrun Hornb, Marcel Meimaa, Douglas Forrestc, Ramona van Heerebeeka, Edward Vissera, Heike Heuerb, Robin Peetersa & Theo Vissera

aErasmus University Medical Center, Rotterdam, The Netherlands; bLeibniz Institute for Age Research/Fritz Lipmann Institute, Jena, Germany; cLaboratory of Endocrinology and Receptor Biology, NIDDK, NIH, Bethesda, Maryland, USA

Background: Patients with a mutation in the thyroid hormone (TH) receptor TRα1 are characterized by growth retardation, delayed bone development, mild cognitive defects and constipation. They also have abnormal TH levels: low FT4, high T3, and low rT3 levels, suggesting an altered peripheral TH metabolism by deiodinases. The type 3 deiodinase (D3) inactivates TH by catalyzing the degradation of T3. D3 is importantly expressed in brain under positive control of T3.

Objective and Hypotheses: From this perspective we hypothesized that changes in serum TH levels in TRα1 patients are due to dysregulation of D3 activity. Our objective was to investigate the role of TRα1 in the regulation of D3 in brain by T3.

Method: We determined the activity of brain D3 as well as serum TH levels in WT mice, mice with a heterozygous dominant-negative mutation in TRα1 (TRα1PV), mice deficient in TRα1 (TRα1KO), mice deficient in TH (PAX8KO), and mice lacking both TH and TRα1 (PAX8/TRα1 DKO). In addition, we studied the D3 promoter activity in vitro.

Results: Compared with WT mice, both TRα1PV and PAX8KO mice showed a 45% reduction in brain D3 activity. D3 activity was 37% higher in TRα1KO than in WT mice. Additional deletion of PAX8 in the TRα1KO background only reduced brain D3 activity by 18%, indicating that D3 activity is predominantly regulated by TRα1. In cultured neurons, transfection of WT TRα1 increased D3 promoter activity in the presence of T3, whereas transfection of TRα1 with the patient’s mutation or of the TRβ1 isoform had no effect.

Conclusion: These findings show that TRα1 plays a major role in the positive regulation of D3 by TH in brain. This suggests that the changes in TH levels in patients with a TRα1 mutation are at least in part due to an impaired D3 activity.